The object of the proposed studies is to examine the effect of tumor growth state and tumor therapy (radiotherapy, chemotherapy, and manipulation of host immune system) on the uptake of gallium-67. Two mouse tumor systems which grow in vivo and in vitro will be employed: the EMT-6 sarcoma-like tumor of the BALB/c mouse and the 6C3HED lymphosarcoma of the C3H mouse. A transformable in vitro cell line, C3H 10 T1/2 mouse fibroblasts, will be used to examine gallium-67 uptake in the same cell type during transformation from a normal to malignant state. The influence of treatment and growth state will be examined first in vitro. Uptake of gallium-67 citrate, iron-59 (ferric) citrate, and 125I-transferrin will be studied and the competing role of stable ferric citrate will be assessed. Analogous uptake experiments will be performed in vivo, where, additionally, uptake of gallium-67 precomplexed to mouse transferrin will be measured and serum iron levels will be quantitated. Variation in uptake of the three labels and the competing role of iron will be interpreted in terms of the applicants' transferrin receptor hypothesis of gallium-67 uptake. The hypothesis views the incorporation of gallium-67 by tumor cells as a multistep process which includes binding of gallium-67 to serum transferrin; binding of the metal-protein complex to a cell surface transferrin receptor; incorporation of the complex into the cell; and binding of gallium-67 to receptor molecules after release from the transferrin. Gallium uptake may be interrupted at any of these steps either by competition from iron or by some other means.